The lifetime risk of heart failure in the United States is 20% and this diagnosis carries a high annual mortality of 13%. Reduction of heart failure mortality and readmission rate has been identified as a major strategic goal within the VA system. Left ventricular assist devices (LVADs) have become a frequently used therapy for patients with the most advanced forms of heart failure. LVADs are used as a bridge to transplant or as permanent therapy. The benefits of restoring normal cardiac output through LVAD support are well described, but our understanding of the effects and possible consequences of LVAD- induced mechanical unloading at the level of the myocardium remains limited. In a subset of patients, LVAD unloading results in sustained improvement of left ventricular function, but the clinical or pathologic features associated with this functional recovery are not well described. We hypothesize that the favorable effects of non-pulsatile LVAD unloading on cardiac function are associated with specific clinical features, specific structural changes at the tissue level and specific alterations in molecular pathways of vascular remodeling, collagen turnover and energy metabolism. The feasibility of serial examination of myocardial tissue in LVAD patients (obtained at the time of LVAD implant and again at the time of explant) with the concurrent ability to serially examine cardiac function (through echocardiography) provides us with a unique opportunity to test this hypothesis directly in humans. We propose to test this hypothesis in a prospective study to be conducted by investigators at the Salt Lake City VAMC and the Richmond VAMC. We have carried out pilot investigations in patients who received LVADs as a bridge to transplant. We have developed protocols for the monitoring of cardiac function and for tissue acquisition, processing and analysis. In particular, we have implemented novel methods of digital histopathology to accurately evaluate a number of remodeling changes in the myocardium. Our preliminary data confirmed that improvement of left ventricular function is seen in approximately 25% of patients. On the tissue level, LVAD unloading resulted in regression of cardiomyocyte hypertrophy and an increase in microvasculature density but also an increase in collagen content. Our preliminary data establishes the feasibility of our study in achieving the stated aims to: 1.To demonstrate that myocardial recovery results from LVAD unloading and can be defined by functional and structural descriptors, 2. To determine whether endothelial to mesenchymal transition (EMT) contributes to structural changes seen in LVAD unloading, and 3. To identify specific metabolic changes associated with recovery of myocardial function. If structural and molecular changes that favor functional myocardial improvement can be identified, this will open the way for identification and testing of therapies which, in combination with LVAD unloading, may enhance the degree of myocardial functional recovery and regeneration in patients with advanced heart failure. Achieving myocardial recovery, if only in a subset of veterans with advanced heart failure, would represent a major therapeutic advance.